Process for producing 1 2 3 triazole compound

ABSTRACT

Disclosed is a process for efficiently producing a compound represented by formula (I):  
                 
 
wherein R 1  represents aryl, amino, alkyl, or alkoxy; R 2  represents a protective group of the carboxylic acid; and R 3  represents an alkali metal, a hydrogen atom, alkyl, aryl, alkylsulfonyl, arylsulfonyl, or trialkylsilyl. This process is characterized by reacting a compound of formula (II) with a compound of formula (III) in the presence of a transition metal compound.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel process for producing1,2,3-triazole compounds useful as a starting material or anintermediate of pharmaceutical products.

2. Background Art

1,2,3-Triazole compounds are useful as a starting material or anintermediate of pharmaceutical products. For example, the compounds canbe utilized as an intermediate in the production of tricyclictriazolobenzoazepine derivatives which are useful as antiallergic agentsas described in WO 99/16770. In a general production process of1,2,3-triazole compounds, an acetylene compound or an olefin compound isreacted with an azide compound to cause a cycloaddition reaction andconsequently to construct a 1,2,3-triazole ring (H. Wamhoff;“Comprehensive Heterocyclic Chemistry,” Pergamon Press, New York (1984),Vol. 5, p. 705).

The cycloaddition reaction of the acetylene compound with the azidecompound is highly versatile, because a wide range of substituents areaccepted to both the acetylene compound and the azide compound.

On the other hand, in the cycloaddition reaction of the olefin compoundwith the azide compound, a special olefin compound having a leavinggroup such as a halogen or a hydroxyl group is provided and isaromatized by an elimination reaction (H. Wamhoff; “ComprehensiveHeterocyclic Chemistry,” Pergamon Press, New York (1984), Vol. 5, p.712). The conversion to the special olefin compound is necessary for useof this cycloaddition reaction so that the production process is long.Furthermore, this cycloaddition reaction is sometimes disadvantageous inthat high-temperature, high-pressure and other conditions should be usedin the elimination reaction for the aromatization.

Heterocycles, vol. 51, p 481 (1999) and J. Med. Chem., vol. 26, p 714(1983) disclose processes in which an olefin compound having no leavinggroup is reacted with an azide compound. This process, however, is notefficient because of low yield.

WO 99/16770 discloses a general method for converting an olefin compoundto an acetylene compound. This method, however, involves a longproduction process and hence is cost-ineffective.

Thus, there is still a need for a process for producing a 1,2,3-triazolecompound from an olefin compound having no leaving group in an efficientand cost-effective manner.

SUMMARY OF THE INVENTION

The present inventors have now found that 1,2,3-triazole compounds canbe efficiently produced by directly reacting an olefin compound havingno leaving group with an azide compound having a substituent in thepresence of a catalytic amount of a transition metal compound. Thepresent inventors have further found that the yield of the product canbe improved by carrying out the reaction in the presence of an oxidizingagent or under an oxygen atmosphere. The present invention has been madebased on such findings.

Accordingly, an object of the present invention is to provide a processwhich can produce a 1,2,3-triazole compound in an efficient andcost-effective manner.

According to the present invention, there is provided a process forproducing a 1,2,3-triazole compound represented by formula (I):

-   -   wherein R¹ represents optionally substituted aryl, optionally        substituted amino, optionally substituted alkyl, or optionally        substituted alkoxy; R² represents a protective group of the        carboxylic acid; and R³ represents an alkali metal, a hydrogen        atom, optionally substituted alkyl, optionally substituted aryl,        optionally substituted alkylsulfonyl, optionally substituted        arylsulfonyl, or trialkylsilyl, the process comprising the step        of:    -   reacting a compound represented by formula (II):        wherein R¹ and R² are as defined above, with an azide compound        represented by formula (III):        R³—N₃  (III)        wherein R³ is as defined above, in the presence of a transition        metal compound.

DETAILED DESCRIPTION OF THE INVENTION

The terms “alkyl” and “alkoxy” as used herein as a group or a part of agroup respectively mean straight chain, branched chain, or cyclic alkyland alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms,unless otherwise specified.

The term “aryl” as used herein means phenyl or naphthyl.

Substituents as one or at least two substituents for the aryl grouprepresented by R¹ include the following substituents (a) to (n):

-   -   (a) a hydrogen atom;    -   (b) a halogen atom;    -   (c) an optionally protected hydroxyl group;    -   (d) formyl;    -   (e) C₁₋₁₂ alkyl;    -   (f) C₂₋₁₂ alkenyl;    -   (g) C₁₋₁₂ alkoxy;    -   (h) —C═N—OR⁴ wherein R⁴ represents a hydrogen atom, C₁₋₆ alkyl,        phenyl C₁₋₄ alkyl, or phenyl;    -   (i) —(CH₂)_(m)—OR⁵ wherein m is an integer of 1 to 4, and R⁵        represents a hydrogen atom, C₁₋₆ alkyl, or phenyl C₁₋₄ alkyl in        which one or more hydrogen atoms on the benzene ring of the        phenylalkyl group is optionally substituted by C₁₋₄ alkyl;    -   (j) —(CH₂)_(k)—COR⁶ wherein k is an integer of 0 to 4, and R⁶        represents a hydrogen atom or C₁₋₄ alkyl;    -   (k) —(CH₂)_(j)—COOR⁷ wherein j is an integer of 0 to 4, and R⁷        represents a hydrogen atom or C₁₋₆ alkyl;    -   (l) —(CH₂)_(p)—NR⁸R⁹ wherein p is an integer of 1 to 4, and R⁸        and R⁹, which may be the same or different, represent (1) a        hydrogen atom, (2) C₁₋₆ alkyl in which the alkyl group is        optionally substituted by amino optionally substituted by C₁₋₄        alkyl, (3) phenyl C₁₋₄ alkyl, (4) —COR¹⁴ wherein R¹⁴ represents        a hydrogen atom or C₁₋₄ alkyl which is optionally substituted by        carboxyl, or (5) —SO₂R¹⁵ wherein R¹⁵ represents C₁₋₄ alkyl or        phenyl in which the phenyl group is optionally substituted by a        halogen atom;    -   (m) —(CH₂)_(q)—CONR¹⁰R¹¹ wherein q is an integer of 0 to 4, and        R¹⁰ and R¹¹, which may be the same or different, represent a        hydrogen atom; a saturated or unsaturated five- to        seven-membered heterocyclic ring in which the heterocyclic ring        is selected from the group consisting of pyridine, imidazole,        oxazole, thiazole, pyrimidine, furan, thiophene, pyrrole,        pyrrolidine, piperidine, tetrahydrofuran, and oxazoline; or C₁₋₆        alkyl in which the alkyl group is optionally substituted by a        saturated or unsaturated five- to seven-membered heterocyclic        ring in which the heterocyclic ring is selected from the group        consisting of pyridine, imidazole, oxazole, thiazole,        pyrimidine, furan, thiophene, pyrrole, pyrrolidine, piperidine,        tetrahydrofuran, and oxazoline; or alternatively R¹⁰ and R¹¹ may        form, together with a nitrogen atom to which they are attached,        a saturated or unsaturated five- to seven-membered heterocyclic        ring in which the heterocyclic ring is selected from the group        consisting of pyridine, imidazole, oxazole, thiazole,        pyrimidine, furan, thiophene, pyrrole, pyrrolidine, piperidine,        tetrahydrofuran, oxazoline, piperazine, morpholine, succinimide,        indole, isoindole, phthalimido, benzothiazole, and        1,1-dioxo-benzothiazole, and is optionally substituted by C₁₋₄        alkyl; and    -   (n) —NR¹²R¹³ wherein R¹² and R¹³, which may be the same or        different, represent a hydrogen atom or —COR¹⁶ wherein R¹⁶        represents a hydrogen atom; C₁₋₆ alkyl; or phenyl which is        optionally substituted by C₁-4 alkyl or C₁₋₆ alkoxy in which the        alkoxy group is optionally substituted by phenyl.

Substituents as one or at least two substituents for the amino grouprepresented by R¹ include: alkyl; aryl; acyl, preferably alkylcarbonyl;and optionally substituted sulfonyl, for example, alkyl optionallysubstituted by phenyl.

Substituents as one or at least two substituents for the alkyl grouprepresented by R¹ include: straight chain alkyl, for example, methyl,ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; branched chain alkyl,for example, isopropyl, isobutyl, tert-butyl, and 3-pentyl; and cyclicC₃₋₇ alkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

Substituents as one or at least two substituents for the alkoxy grouprepresented by R¹ include: halogen atoms; hydroxyl; cyano; C₃₋₇cycloalkyl; phenyl; C₁₋₄ alkoxy; phenoxy; and amino which is optionallysubstituted by C₁₋₄ alkyl.

In a preferred embodiment of the present invention, R¹ representsphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,6-amino-3,4-dimethoxyphenyl, 3,4-dimethoxy-phenylamino, ethoxyl, ormethoxyl, more preferably 3,4-dimethoxyphenyl,3,4-dimethoxy-phenylamino, or methoxyl.

In the present invention, preferred protective groups of the carboxylicacid represented by R² include, for example, methyl, ethyl, tert-butyl,benzyl, 4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl,tert-butyldimethylsilyl, triphenylsilyl, 2-phenylsulfonylethyl,2-methoxycarbonylethyl, 2-cyanoethyl, and 2-trimethylsilylethyl, morepreferably methyl, ethyl, tert-butyl, benzyl, 4-methoxybenzyl,diphenylmethyl, 4-nitrobenzyl, tert-butyidimethylsilyl, triphenylsilyl,2-phenylsulfonylethyl, 2-methoxycarbonylethyl, 2-cyanoethyl, and2-trimethylsilylethyl, particularly preferably ethyl.

In the present invention, substituents for the alkyl, alkylsulfonyl, andarylsulfonyl groups represented by R³ include phenyl optionallysubstituted by nitro or alkoxy.

Examples of preferred groups as R³ include methyl, ethyl, benzyl,p-nitrobenzyl, p-methoxybenzyl, methylsulfonyl, ethylsulfonyl,benzylsulfonyl, p-nitrobenzylsulfonyl, p-methoxybenzylsulfonyl, phenyl,p-methoxyphenyl, p-nitrophenyl, naphthyl, trimethylsilyl, triethylsilyl,tert-butyldimethylsilyl, triphenylsilyl, tert-butyidiphenylsilyl, alkalimetal, and a hydrogen atom, more preferably sodium, potassium, ahydrogen atom, trimethylsilyl, triethylsilyl, t-butyidimethylsilyl,p-methoxybenzyl, and toluenesulfonyl, particularly preferably sodium anda hydrogen atom.

Reaction Conditions

While in the present invention proportions of the compounds used are notparticularly limited and may be properly determined, the amount of theazide compound of formula (III) used is preferably 0.5 to 20 molarequivalents, more preferably 1 to 3 molar equivalents, based on thecompound of formula (II). The reaction is carried out in a suitablesolvent at room temperature or with heating. The solvent usable in thereaction is not particularly limited so far as the solvent does notretard the progress of the reaction, and examples thereof include: alkylalcohols such as methanol, ethanol, isopropanol and butanol; alkylethers such as tetrahydrofuran, dioxane and diphenyl ether; halogenatedhydrocarbons such as methylene chloride, chloroform, and1,1,2,2-tetrachloroethane; aromatic hydrocarbons such as benzene,toluene and xylene; ketones such as acetone and 2-butanone; aproticpolar solvents such as N,N-dimethylformamide, dimethylsulfoxide, andacetonitrile; or water. These solvents may be used solely or as amixture of two or more. The reaction temperature is preferably −20° C.to the boiling point of the solvent, more preferably 0° C. to theboiling point of the solvent. The reaction time is preferably 10 min to48 hr, more preferably 2 to 15 hr.

Transition Metal Compound

In the present invention, the transition metal compound used in thereaction is preferably copper(I) chloride, copper(I) bromide, copper(I)iodide, iron(III) bromide, iron(III) chloride and iron(III) iodide, morepreferably copper(I) chloride and iron(III) chloride. Further, hydratesof these compounds may also be used.

Oxidizing Agents

The process according to the present invention, when carried out in thepresence of an oxidizing agent, can provide compounds of formula (I) inimproved yields, and, hence, the utilization of the oxidizing agent ispreferred. Preferred oxidizing agents include, for example, salts ofhalogen oxy-acids such as chlorate, chlorite, bromate and iodate,organic peracids such as persulfate, hydrogen peroxide, peracetic acidand 4-chloroperbenzoic acid and metallic oxides such as manganesedeoxide and chromic acid. More preferred are sodium chlorate and sodiumbromate. The amount of the oxidizing agent used is preferably 0.1 to 5molar equivalents, more preferably 0.4 to 1.5 molar equivalents, basedon the compound of formula (II). The utilization of oxygen can alsoprovide compounds of formula (I) in improved yields. In this case,preferably, the reaction is carried out under an oxygen atmosphere untilthe reaction is completed, or alternatively the supply of oxygen intothe reaction solution is continued until the reaction is completed.

Optionally after reaction terminating treatment, the compound producedby the process of the present invention can be easily purified byconventional purification methods such as recrystallization,chromatography, and distillation.

EXAMPLES

The present invention is further illustrated by the following Examplesthat are not intended as a limitation of the invention.

Example 1 Ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate

Copper(I) chloride (7.5 mg, 0.075 mmol) was added at room temperature toa solution (1.0 mL) of sodium azide (74 mg, 1.1 mmol) inN,N-dimethylformamide. A solution (1.5 mL) of ethyl4-(3,4-dimethoxyphenyl)-4-oxo-2-butenate (200 mg, 0.76 mmol) inN,N-dimethylformamide was added to this mixed solution at 5° C. Thetemperature of the reaction solution was raised to room temperaturebefore the reaction solution was stirred for 8 hr. After the completionof the reaction, the reaction solution was poured into iced water, andthe mixture was extracted with a saturated aqueous sodiumhydrogencarbonate solution. The aqueous layer was adjusted to pH 1.8 bythe addition of 2 N hydrochloric acid, followed by extraction with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was then removed by evaporation under the reduced pressure.The oil thus obtained was dried in vacuo to give ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (149 mg, 65%).

¹H-NMR (CDCl₃): δ 1.70 (3H, t), 3.90 (3H, s), 3.93 (3H, s), 4.28 (2H,q), 6.84 (1H, d), 7.39 (1H, dd), 7.60 (1H, d).

¹³C-NMR (CDCl₃): δ 13.9, 56.1, 56.2, 62.2, 109.9, 110.8, 126.3, 129.3,149.1, 154.3, 160.1, 185.8.

Example 2 Ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate

Copper(I) chloride (190 mg, 1.91 mmol) was added at room temperature toa solution (40 mL) of sodium azide (1.84 g, 28.3 mmol) inN,N-dimethylformamide, and the air in the system was replaced by oxygen.A solution (10 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate(2.50 g, 9.46 mmol) in N,N-dimethylformamide was added to this mixedsolution at 5° C. over a period of 30 min. The temperature of thereaction solution was raised to room temperature before the reactionsolution was stirred for 3 hr. Thereafter, the reaction temperature waslowered to 5° C., and a solution (10 mL) of ethyl4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g, 9.46 mmol) inN,N-dimethylformamide was added thereto. The temperature of the reactionsolution was raised to room temperature before the reaction solution wasstirred for 4 hr. After the completion of the reaction, the reactionsolution was poured into iced water (75 mL), and sodium nitrite (636 mg,9.22 mmol) was added thereto. The mixture was adjusted to pH 1.8 by theaddition of 6 N sulfuric acid and was extracted with ethyl acetate. Tothe organic layer was added 5 wt % brine. The mixture was adjusted to pH1.5 by the addition of 1 N hydrochloric acid, followed by separation.The organic layer was dried over anhydrous sodium sulfate, and thesolvent was removed by evaporation under the reduced pressure. Toluenewas added to the residue, and the solvent was removed by evaporationunder the reduced pressure. The resultant crystal was washed withtoluene and was then dried under the reduced pressure to give ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (4.71 g, 81%).

Example 3 Ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate

Iron(III) chloride (309 mg, 1.90 mmol) was added at room temperature toa solution (37.5 mL) of sodium azide (1.84 g, 28.3 mmol) inN,N-dimethylformamide. A solution (25 mL) of ethyl4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g, 9.46 mmol) inN,N-dimethylformamide was then added to the mixture at 5° C. under anoxygen atmosphere. The temperature of the reaction solution was raisedto room temperature before the reaction solution was stirred for 3 hr.Thereafter, ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (2.50 g,9.46 mmol) was added to the reaction solution at room temperature, andthe mixture was stirred for additional 4 hr. After the completion of thereaction, the reaction solution was poured into iced water, and sodiumnitrite (636 mg, 9.22 mmol) was added thereto. The mixture was adjustedto pH 2 by the addition of 1 N hydrochloric acid and was extracted withethyl acetate, and 5 wt % brine was then added. The mixture was adjustedto pH 2.0 by the addition of 1 N hydrochloric acid, followed byseparation. The organic layer was dried over anhydrous sodium sulfate,and the solvent was then removed by evaporation under the reducedpressure. Toluene was added to the residue, and toluene was removed byevaporation under the reduced pressure. The resultant crystal wascollected by filtration, was washed with toluene, and was then driedunder the reduced pressure to give ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (5.08 g, 88%).

Example 4 Ethyl 4-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-5-carboxylate

Sodium azide (4.87 g, 75 mmol), sodium chlorate (2.90 g, 27 mmol), and a37% aqueous ferric chloride solution (1.49 g, 3 mmol) were added toN,N-dimethylformamide (36 mL), the mixed solution was heated to 40° C.,and a mixed solution previously prepared by adding ethyl4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate (18 g, 68 mmol) toN,N-dimethylformamide (36 mL) and then dissolving them each other at 50°C. was added dropwise thereto. After the completion of the dropwiseaddition, a reaction was allowed to proceed at 40° C. for one hr, and areaction was further allowed to proceed at 65° C. for one hr. After thecompletion of the reaction, the reaction solution was cooled to 5° C.,and acetonitrile (7 mL) and an aqueous solution of sodium nitrite (1.18g, 17 mmol) in water (25 mL) were successively added dropwise thereto.The mixture was adjusted to pH 1.5 by the addition of a 3 M aqueoussulfuric acid solution. The mixture was stirred at 5° C. for one hr, andethyl acetate (198 ml) was then added thereto, followed by separation.The organic layer was washed three times with 5% brine, was dried overanhydrous magnesium sulfate, and was filtered. The filtrate wasconcentrated under the reduced pressure to precipitate crystals. Toluene(90 mL) was added to the residue of the concentration, and the crystalswere aged at 5° C. for 12 hr. The crystals were collected by filtration,were then washed with toluene, and were dried under the reduced pressureto give 17.15 g of a light yellow powder (yield 82.5%).

Example 5 Ethyl 1H-1,2,3-triazole-4,5-dicarboxylate

Copper(I) chloride (288 mg, 2.91 mmol) was added at room temperature toa solution (52.5 mL) of sodium azide (2.83 g, 43.5 mmol) inN,N-dimethylformamide. A solution (5.0 mL) of diethyl fumarate (2.50 g,14.5 mmol) in N,N-dimethylformamide was added to the mixture at 5° C.under an oxygen atmosphere. The temperature of the reaction solution wasraised to room temperature before the reaction solution was stirred for12 hr. Thereafter, the reaction solution was cooled to 5° C., and asolution (5.0 mL) of diethyl fumarate (2.50 g, 14.5 mmol) inN,N-dimethylformamide was added thereto, and the temperature of thereaction solution was raised to room temperature before the reactionsolution was stirred for 12 hr. After the completion of the reaction,the reaction solution was poured into iced water (75 mL), and sodiumnitrite (1.00 g, 14.5 mmol) was added thereto. The mixture was adjustedto pH 1.8 by the addition of 2 N hydrochloric acid and was extractedwith ethyl acetate. Saturated brine was then added to the organic layer,and the mixture was adjusted to pH 1.0 by the addition of 1 Nhydrochloric acid, followed by separation. The organic layer was driedover anhydrous sodium sulfate, and the solvent was then removed byevaporation under the reduced pressure. The oil thus obtained was driedunder the reduced pressure to give ethyl1H-1,2,3-triazole-4,5-dicarboxylate (5.96 g, 96%).

¹H-NMR (CDCl₃): δ 1.39 (6H, t), 4.44 (4H, q).

Example 6 Ethyl5-(3,4-dimethoxy-phenylcarbamoyl)-1H-1,2,3-triazole-4-carboxylate

Copper(I) chloride (35 mg, 0.35 mmol) was added at room temperature to asolution (50 mL) of sodium azide (690 mg, 10.6 mmol) inN,N-dimethylformamide, and the air in the system was replaced by oxygen.This mixed solution was cooled to 5° C., and a solution (30 mL) of ethyl4-(3,4-dimethoxy-anilid)-4-oxo-2-butenoate (1.00 g, 3.58 mmol) inN,N-dimethylformamide was added thereto over a period of 30 min. Thetemperature of the reaction solution was raised to room temperaturebefore the reaction solution was stirred for 2 days. After thecompletion of the reaction, the reaction solution was poured into icedwater, and sodium nitrite (494 mg, 7.16 mmol) was added thereto. Themixture was adjusted to pH 1.5 by the addition of 2 N hydrochloric acidand was extracted with ethyl acetate. Saturated brine was then added tothe organic layer, and the mixture was adjusted to pH 1.5 by theaddition of 1 N hydrochloric acid, followed by separation. The organiclayer was dried over anhydrous sodium sulfate, and the solvent was thenremoved by evaporation to about 20 mL under the reduced pressure. Theprecipitated solid was collected by filtration, was washed with ethylacetate, and was then dried under the reduced pressure to give ethyl5-(3,4-dimethoxy-phenylcarbamoyl)-1H-1,2,3-triazole-4-carboxylate (888mg, 77%).

¹H-NMR (DMSO-d₆): δ 1.24 (3H, t), 3.74 (6H, s), 4.32 (2H, q), 6.94 (1H,d), 7.20 (1H, dd), 7.38 (1H, d), 10.70 (1H, br-s).

Reference Example Ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate

A solution (3.0 mL) of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoate(104 mg, 0.39 mmol) in N,N-dimethylformamide was added to a solution(5.0 mL) of sodium azide (40 mg, 0.62 mmol) in N,N-dimethylformamide at5° C. The temperature of the reaction solution was raised to roomtemperature before the reaction solution was stirred for 6 hr. After thecompletion of the reaction, iced water (10 mL) was added to the reactionsolution, and the mixture was washed with ethyl acetate. The aqueouslayer was then adjusted to pH 1.5 by the addition of 2 N hydrochloricacid, followed by extraction with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was then removed byevaporation under the reduced pressure. The oil thus obtained was driedin vacuo to give ethyl5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate (63 mg, yield52%).

1. A process for producing a 1,2,3-triazole compound represented byformula (I):

wherein R¹ represents optionally substituted aryl, optionallysubstituted amino, optionally substituted alkyl, or optionallysubstituted alkoxy; R² represents a protective group of the carboxylicacid; and R³ represents an alkali metal, a hydrogen atom, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedalkylsulfonyl, optionally substituted arylsulfonyl, or trialkylsilyl,said process comprising the step of: reacting a compound represented byformula (II):

wherein R¹ and R² are as defined above, with an azide compoundrepresented by formula (III):R³—N₃  (III) wherein R³ is as defined above, in the presence of atransition metal compound.
 2. The process according to claim 1, whereinthe transition metal compound is copper(I) chloride or iron(III)chloride.
 3. The process according to claim 1 or 2, wherein the reactionis carried out in the presence of an oxidizing agent or under an oxygenatmosphere.
 4. The process according to claim 3, wherein the oxidizingagent is sodium chlorate or sodium bromate.
 5. The process according toany one of claims 1 to 4, wherein R¹ represents 3,4-dimethoxyphenyl,3,4-dimethoxy-phenylamino, or methoxyl, R² represents ethyl, and R³represents sodium or a hydrogen atom.